Colorectal cancer is the most common visceral cancer in the United States. Each year, more than 160,000 new cases of colorectal cancer are detected which account for more than 60,000 deaths. The national incidence of colorectal cancer appears to be on the rise, as it increased by 9.4% from 1973 to 1986 based on a sample of 10% of the U.S. population. Unfortunately, the five-year survival rate has not improved significantly over the past four decades. As prognosis worsens with more advanced cancers, many physicians and several national medical societies advocate routine screening to increase early stage detection. However, while the rationale for screening is sound, such efforts at secondary prevention require an enormous use of medical resources and have not been shown to be effective in a general population.
Colorectal cancer provides unique opportunities for primary intervention among human malignancies because it progresses through clinically recognizable stages from normal mucosa through enlarging and increasingly dysplastic polyps which eventuate in carcinoma. Support for the adenoma to carcinoma sequence is provided by epidemiological studies, shared genetic properties of both adenomas and carcinomas, and the natural history of adenomas as observed in patients with familial adenomatous polyposis. Nicholson M L, et al., "Increased Cell Membrane Arachidonic Acid in Experimental Colorectal Tumors," Gut 32:413-8 (1991); Fearon E R, et al., "Colonal Analysis of Human Colorectal Tumors," 238 Science 193 (1987); and Bussey H J R, "Familial Polyposis Coli," Family Studies, Histopathology, Differential Diagnosis, and Results of Treatment (Johns Hopkins University Press, Baltimore 1975). Genetic factors appear to mediate the development of colonic adenomas in familial adenomatous polyposis (FAP), for example, and may also play a role in the development of sporadic adenomas and carcinomas. In addition, there is evidence for an accumulating series of genetic deletions and mutations including known oncogenes and tumor suppressors, that accompany the transition from normal mucosa to adenoma to carcinoma.
The precursor relationship of colorectal adenoma to carcinoma and the high prevalence of adenomas makes them an attractive target in chemoprevention trials. The prevalence increases with age in moderate and high risk populations, reaching 20-40% at the age of 50-60 years, and 50% or more for individuals older than 70 years. The steepest increase in adenoma prevalence occurs between the ages of 50-59. However, removal of polyps does not change the pathogenetic milieu responsible for their growth and development. The recurrence rate for colorectal adenomas has been variably reported, but most studies document an adenoma recurrence rate of 20-60% by two years. Nava H, et al., "Follow-up Colonoscopy in Patients With Colorectal Adenomatous Polyps," 30 Dis. Colon Rectum 465 (1987); Olsen H W, et al., "Review of Recurrent Polyps in Cancer in 500 Patients With Initial Colonoscopy for Polyps," 31 Dis. Colon Rectum 222 (1988); Williams C B and Macrae F A, "The St. Mark's Neoplastic Polyp Follow-up Study," 10 Front. Gastrointest. Res. 1226 (1986). Winawer recently reported that 28% of patients who had newly diagnosed adenomas removed by colonoscopy had additional polyps detected at a one-year follow-up examination, and of those patients, 22% had new adenomatous polyps again detected on examination two years later. Winawer S J, et al., "Randomized Comparison of Surveillance Intervals After Colonoscopic Removal of Newly Diagnosed Adenomatous Polyps," 328 New Engl. J. Med. 901 (1993). Patients who have undergone surgical resection of a primary colorectal cancer have also been shown to be at high risk of developing metachronous adenomas. Olsen H W, et al., "Review of Recurrent Polyps in Cancer in 500 Patients With Initial Colonoscopy for Polyps," 31 Dis. Colon Rectum 222 (1988).
Several studies have focused attention on bile acids as a potential mediator of the dietary influence on colorectal cancer risk. Hofmann A F, "Chemistry and Enterohepatic Circulation of Bile Acids," Hepatology 4S-14S (1984). Bile acids are important detergents for fat solubilization and digestion in the proximal intestine. Specific transport processes in the apical domain of the terminal ileal enterocyte and basolateral domain of the hepatocyte account for the efficient conservation in the enterohepatic circulation. Only a small fraction of bile acids enter the colon; however, perturbations of the cycling rate of bile acids by diet (e.g., fat) or surgery (e.g., cholecystectomy) may increase the fecal bile acid load and perhaps account for the associated increased risk of colon cancer. Hill M J, "Bile Flow and Colon Cancer," 238 Mutation Review 313 (1990). Studies linking perturbations in fecal bile acids with human colon cancer, however, have been inconsistent and controversial. The inconsistencies could stem from differences in the populations studied, patient selection, or methodologic artifacts in measuring fecal bile acid excretion.
Thus, chemoprevention of colorectal cancer, by dietary or pharmacologic intervention, remains to be established. There is a continuing need, therefore, to develop new chemopreventative treatments for colorectal adenomas.